Development of novel therapeutic strategies for uterine leiomyoma

• Project/Area Number: 16K11107
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Obstetrics and gynecology
• Research Institution: Kanazawa University
• Principal Investigator: Ono Masanori 金沢大学, 附属病院, 講師 (70348712)
• Co-Investigator(Kenkyū-buntansha): 丸山 哲夫 慶應義塾大学, 医学部(信濃町), 准教授 (10209702)
• Project Period (FY): 2016-04-01 – 2019-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000); Fiscal Year 2018: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2017: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2016: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
• Keywords: 子宮筋腫 / 子宮 / 組織幹細胞 / 子宮筋 / 子宮筋腫幹細胞 / エストロゲン / プロゲステロン / 生殖医学

Outline of Final Research Achievements

Tissue-specific stem cells constitute a subset of cells residing in normal adult tissues. Estrogen and progesterone stimulate the growth of leiomyomas. Estrogen, together with its receptor ERα, enables progesterone action via induction of progesterone receptor expression. Progesterone induces the growth of leiomyoma by regulation of a set of key genes that control proliferation and apoptosis.The WNT/β-catenin pathway comprises a key component of this signaling system. The majority of medical treatments currently available for leiomyoma works by inhibiting estrogen or progesterone production or action, but tumors tend to regrow once treatment is stopped. We showed that uterine leiomyoma stem cells involve IGF2 and Insulin Receptor A. Targeting stem cells and their paracrine interactions with more differentiated cell populations within leiomyoma may lead to the development of more effective therapeutics for uterine leiomyoma.

Academic Significance and Societal Importance of the Research Achievements

子宮筋腫の発育に関わる因子として、これまで性ステロイド，Transforming growth factor-β/SMAD, Retinoic acid, PPARγが報告されてきた。今回我々は、ヒト子宮平滑筋の発生・分化・修復の機構とその異常、また子宮筋腫の病態メカニズムにWNT/β-cateninシグナル、IGF2とInsulin Receptor A のシグナルが関わっていることを明らかにした。これまで子宮筋腫の治療は性ステロイドに働きかけるものが使用され、使用終了後には子宮筋腫が増悪してしまっていたが、当研究成果によりは子宮筋腫の新たな効果的な治療薬開発に役立てることができる。

Research Products

• [Int'l Joint Research] ノースウェスタン大学(米国)
• [Int'l Joint Research]
• [Int'l Joint Research] ノースウェスタン大学(米国)
• [Journal Article] Twin anemia-polycythemia sequence with blood chimerism in monochorionic dizygotic opposite-sex twins (2019)
  • Author(s): Suzuki Takuma、Kagami Kyosuke、Mitani Yusuke、Yamazaki Rena、Ono Masanori、Fujiwara Hiroshi
  • Journal Title: Journal of Obstetrics and Gynaecology Research Volume: 2019 Issue: 6 Pages: 1-4
  • DOI: 10.1111/jog.13949
  • Peer Reviewed / Open Access
• [Journal Article] Factors Regulating Human Extravillous Trophoblast Invasion: Chemokine-peptidase and CD9-integrin Systems (2018)
  • Author(s): Fujiwara Hiroshi、Matsumoto Hisanori、Sato Yukiyasu、Horie Akihito、Ono Masanori、Nakamura Mitsuhiro、Mizumoto Yasunari、Kagami Kyosuke、Fujiwara Tomoko、Hattori Akira、Maida Yoshiko、Daikoku Takiko、Imakawa Kazuhiko、Araki Yoshihiko
  • Journal Title: Current Pharmaceutical Biotechnology Volume: 19 Issue: 10 Pages: 764-770
  • DOI: 10.2174/1389201019666181029164906
  • Peer Reviewed
• [Journal Article] Three-dimensional evaluation of murine ovarian follicles using a modified CUBIC tissue clearing method. (2018)
  • Author(s): Kagami K., Shinmyo Y., Ono M., Kawasaki H. and Fujiwara H.
  • Journal Title: Reproductive Biology and Endocrinology Volume: 16 Issue: 1 Pages: 72-72
  • DOI: 10.1186/s12958-018-0381-7
  • Peer Reviewed / Open Access
• [Journal Article] Time Restriction of Food Intake During the Circadian Cycle Is a Possible Regulator of Reproductive Function in Postadolescent Female Rats. (2018)
  • Author(s): Fujiwara T, Nakata R, Ono M, Mieda M, Ando H, Daikoku T, Fujiwara H.
  • Journal Title: Curr Dev Nutr Volume: 3 Issue: 4 Pages: 1-7
  • DOI: 10.1093/cdn/nzy093
  • Peer Reviewed / Open Access
• [Journal Article] Successful detection of SRY gene via fine needle biopsy: A case of extragenital gestational choriocarcinoma in the kidney (2017)
  • Author(s): Orisaka Shunsuke、Kagami Kyosuke、Mizumoto Yasunari、Koda Wataru、Ono Masanori、Nakamura Mitsuhiro、Fujiwara Hiroshi
  • Journal Title: MOLECULAR CLINICAL ONCOLOGY Volume: 7 Pages: 1057-1060
  • DOI: 10.3892/mco.2017.1460
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Dual expression of immunoreactive estrogen receptor β and p53 is a potential predictor of regional lymph node metastasis and postoperative recurrence in endometrial endometrioid carcinoma (2017)
  • Author(s): Obata Takeshi、Nakamura Mitsuhiro、Mizumoto Yasunari、Iizuka Takashi、Ono Masanori、Terakawa Jumpei、Daikoku Takiko、Fujiwara Hiroshi
  • Journal Title: PLOS One Volume: 12 Issue: 11 Pages: 0188641-0188641
  • DOI: 10.1371/journal.pone.0188641
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Subserous invasion of VEGF-C-producing cancer cells is a possible risk factor for ileal ulceration in the non-metastatic mucosal layer during bevacizumab-combined chemotherapy for recurrent ovarian cancer: A case report (2017)
  • Author(s): Matsumoto Takeo、Mizumoto Yasunari、Nakade Kyohei、Obata Takeshi、Matsuoka Ayumi、Myojo Subaru、Ono Masanori、Nakamura Mitsuhiro、Fujiwara Hiroshi
  • Journal Title: MOLECULAR CLINICAL ONCOLOGY Volume: 7 Issue: 5 Pages: 820-824
  • DOI: 10.3892/mco.2017.1403
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Three-dimensional visualization of intrauterine conceptus through the uterine wall by tissue clearing method (2017)
  • Author(s): Kagami Kyosuke、Shinmyo Yohei、Ono Masanori、Kawasaki Hiroshi、Fujiwara Hiroshi
  • Journal Title: SCIENTIFIC REPORTS Volume: 7 Issue: 1 Pages: 5964-5964
  • DOI: 10.1038/s41598-017-06549-6
  • NAID: 120006374152
  • Peer Reviewed / Open Access
• [Journal Article] Giant fetal hydrometrocolpos associated with cloacal anomaly causing postnatal respiratory distress (2017)
  • Author(s): Kanda Tatsuhito、Iizuka Takashi、Yamazaki Rena、Iwadare Junpei、Ono Masanori、Fujiwara Hiroshi
  • Journal Title: JOURNAL OF OBSTETRICS GYNAECOLOGY RESEARCH Volume: 43 Issue: 11 Pages: 1769-1772
  • DOI: 10.1111/jog.13433
  • NAID: 120006343947
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] APOBEC3G is increasingly expressed on the human uterine cervical intraepithelial neoplasia along with disease progression (2017)
  • Author(s): Iizuka Takashi、Wakae Kousho、Nakamura Mitsuhiro、Kitamura Koichi、Ono Masanori、Fujiwara Hiroshi、Muramatsu Masamichi
  • Journal Title: AMERICAN JOURNAL OF REPRODUCTIVE IMMUNOLOGY Volume: 78 Issue: 4 Pages: 111-111
  • DOI: 10.1111/aji.12703
  • Peer Reviewed / Open Access
• [Journal Article] Platelet-derived microparticles and soluble factors differentially regulate human endometrial epithelial cell movement (2017)
  • Author(s): Suginami K, Sato Y, Horie A, Matsumoto H, Tani H, Mizumoto Y, Ono M, Matsuoka A, Kyo S, Araki Y, Konishi I, Fujiwara H
  • Journal Title: Am J Reprod Immunol Volume: Feb 7 Issue: 4 Pages: 12641-12641
  • DOI: 10.1111/aji.12641
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Paracrine Pathways in Uterine Leiomyoma Stem Cells Involve Insulinlike Growth Factor 2 and Insulin Receptor A (2017)
  • Author(s): Moravek Molly B.、Yin Ping、Coon John S.、Ono Masanori、Druschitz Stacy A.、Malpani Saurabh S.、Dyson Matthew T.、Rademaker Alfred W.、Robins Jared C.、Wei Jian-Jun、Kim J. Julie、Bulun Serdar E.
  • Journal Title: JOURNAL OF CLINICAL ENDOCRINOLOGY AND METABOLISM Volume: 102 Issue: 5 Pages: 1588-1595
  • DOI: 10.1210/jc.2016-3497
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Paracrine Pathways in Uterine Leiomyoma Stem Cells Involve Insulin-like Growth Factor-2 and Insulin Receptor-A (2017)
  • Author(s): Moravek MB, Yin P, Ono M, Coon JS 5th, Dyson MT, Navarro A, Marsh EE, Chakravarti D, Kim JJ, Wei JJ, Bulun SE
  • Journal Title: THE JOURNAL OF CLINICAL ENDOCRINOLOGY AND METABOLISM Volume: 印刷中
  • Peer Reviewed / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Platelet-derived microparticles and soluble factors differentially regulate human endometrial epithelial cell movement (2017)
  • Author(s): Suginami K, Sato Y, Horie A, Matsumoto H, Tani H, Mizumoto Y, Ono M, Matsuoka A, Kyo S, Araki Y, Konishi I, Fujiwara H
  • Journal Title: AMERICAN JOURNAL OF REPRODUCTIVE IMMUNOLOGY Volume: 印刷中
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Short, severe dizziness attacks in a pregnant woman with type I ARNOLD-Chiari malformation (2016)
  • Author(s): Ono M, Kojima A, Shirahashi M, Noda S, Akiba Y, Nishijima S, Amagata T, Ikeda T, Yakubo K, Fukuiya T
  • Journal Title: J Obstet Gynaecol Volume: 36 Pages: 430-431
  • Peer Reviewed
• [Journal Article] Dicephalus Parapagus Conjoined Twins Diagnosed by First-Trimester Ultrasound (2016)
  • Author(s): Watanabe K, Ono M, Shirahashi M, Ikeda T, Yakubo K
  • Journal Title: Case Rep Obstet Gynecol. Volume: －
  • Peer Reviewed
• [Journal Article] Laparoscopic repair of an indirect inguinal hernia containing a fallopian tube in an adult woman (2016)
  • Author(s): Shirahashi M, Ono M, Yokoyama N, Okamoto N, Motomura Y, Ikeda T, Yakubo K
  • Journal Title: Gynecology and minimally Invasive Therapy Volume: 5 Pages: 94-95
  • Peer Reviewed
• [Presentation] 子宮頸部の炎症はAPOBEC3G発現を誘導しCINの進行に影響しうる (2018)
  • Author(s): 飯塚 崇, 若江 亨祥, 中村 充宏, 小野 政徳, 村松 正道, 藤原 浩
  • Organizer: 日本性感染症学会
• [Presentation] 生殖生物学研究のためのイメージング技術と応用 マウス妊娠子宮の透明化と3次元画像構築によるfetomaternal interfaceの解析 (2018)
  • Author(s): 鏡 京介, 小野 政徳, 飯塚 崇, 松本 多圭夫, 小幡 武司, 松岡 歩, 藤原 浩
  • Organizer: 日本組織細胞化学会総会・学術集会
• [Presentation] CRISPR/CAS9システムによりMED12変異を導入したヒト子宮筋腫モデルの開発の試み (2018)
  • Author(s): 高尾 知佳, 丸山 哲夫, 小野 政徳, 内田 浩, 升田 博隆, 内田 明花, 三木 史恵, 片倉 慧美, 吉政 佑之, 藤原 浩, 田中 守, 青木 大輔
  • Organizer: 日本産科婦人科学会学術講演会
• [Presentation] APOBEC3Gの発現は子宮頸部異形成の進行に伴い上昇する (2018)
  • Author(s): 飯塚 崇, 中村 充宏, 小野 政徳, 藤原 浩
  • Organizer: 日本産科婦人科学会学術講演会
• [Presentation] 出生前より周産期良性型低ホスファターゼ症を疑い,出生後早期より酵素補充療法を開始した一例 診断から生後8ヵ月の経過 (2018)
  • Author(s): 石島 有華, 飯塚 崇, 小野 政徳, 山崎 玲奈, 保野 由紀子, 桝本 咲子, 鏡 京介, 岩垂 純平, 明星 須晴, 水本 泰成, 中村 充宏, 藤原 浩
  • Organizer: 日本産科婦人科学会学術講演会
• [Presentation] 子宮体部類内膜癌におけるリンパ節転移および術後再発の予測因子の解析 (2018)
  • Author(s): 小幡 武司, 中村 充宏, 飯塚 崇, 小野 政徳, 水本 泰成, 藤原 浩
  • Organizer: 日本産科婦人科学会学術講演会
• [Presentation] マウス妊娠子宮の透明化と内部構造の3次元画像構築 (2018)
  • Author(s): 鏡 京介, 飯塚 崇, 松本 多圭夫, 小幡 武司, 松岡 歩, 折坂 俊介, 岩垂 純平, 山崎 玲奈, 小野 政徳, 藤原 浩
  • Organizer: 日本産科婦人科学会学術講演会
• [Presentation] 続発性無月経の診断と治療 (2018)
  • Author(s): 小野 政徳
  • Organizer: 日本産科婦人科学会学術講演会
• [Presentation] マウス妊娠子宮の透明化と3次元画像構築 (2017)
  • Author(s): 鏡 京介, 小野 政徳, 新明 洋平, 河崎 洋志, 藤原 浩
  • Organizer: 日本生殖医学会
• [Presentation] マウス卵巣顆粒膜細胞におけるActivation induced cytidine deaminase(AID)の発現の検討 (2017)
  • Author(s): 飯塚 崇, 若江 享祥, 喜多村 晃一, 小野 政徳, 村松 正道, 藤原 浩
  • Organizer: 日本生殖医学会
• [Presentation] 母体の血中hCG異常高値を示し，甲状腺の機能異常をきたした巨大胎盤血管腫の1例 (2017)
  • Author(s): 山崎 玲奈, 桝本 咲子, 岩垂 純平, 保野 由紀子, 飯塚 崇, 鏡 京介, 小野 政徳, 藤原 浩
  • Organizer: 日本周産期・新生児医学会
• [Presentation] 胎児腹水の原因と大網浮遊像の所見についての検討 (2017)
  • Author(s): 飯塚 崇, 山崎 玲奈, 保野 由紀子, 桝本 咲子, 三谷 裕介, 酒井 清祥, 岩崎 秀紀, 鏡 京介, 小野 政徳, 藤原 浩
  • Organizer: 北日本産科婦人科学会
• [Presentation] 研修病院におけるJoel-Cohen変法による帝王切開術の有用性についての検討 (2017)
  • Author(s): 鈴木 拓馬, 小野 政徳, 鏡 京介, 飯塚 崇, 桝本 咲子, 保野 由紀子, 山崎 玲奈, 藤原 浩
  • Organizer: 北日本産科婦人科学会
• [Presentation] Role of stem cells in pathophysiology of uterine leiomyoma (2016)
  • Author(s): Ono M, Maruyama T, Tanaka M, Aoki D, Bulun SE
  • Organizer: 5th Asian Conference on Endometriosis
  • Place of Presentation: Osaka
  • Year and Date: 2016-09-22
  • Int'l Joint Research / Invited
• [Presentation] Somatic Stem Cells in the Myometrium and Tumor-Initiating Cells in Leiomyomas (2016)
  • Author(s): Ono M, Maruyama T, Tanaka M, Aoki D, Bulun SE
  • Organizer: The 8th Japan-Korea ART Conference
  • Place of Presentation: Yokohama
  • Int'l Joint Research
• [Book] Uterine Fibroids and Adenomyosis (2018)
  • Author(s): Masanori Ono, Tetsuo Maruyama, Hiroshi Fujiwara, Serdar E. Bulun
  • Total Pages: 173
  • Publisher: Springer
  • ISBN: 9789811071669
• [Book] 胎児発育不全 (2018)
  • Author(s): 小野 政徳、飯塚 崇、藤原 浩
  • Total Pages: 196
  • Publisher: 中外医学社
  • ISBN: 9784498060906
• [Book] 成人看護［3］ 第14版 (2018)
  • Author(s): 石毛 尚代、小野政徳
  • Total Pages: 374
  • Publisher: 医学書院
  • ISBN: 9784260031790
• [Book] ホルモンQ&A ホルモン治療中の出血対策方法にはどのような方法がありますか (2017)
  • Author(s): 小野 政徳, 藤原 浩
  • Total Pages: 3
  • Publisher: HORMONE FRONTIER IN GYNECOLOGY
• [Book] ホルモンQ&A 乳癌でホルモン治療中の若年女性患者を診察する際に留意すべきことを教えてください (2017)
  • Author(s): 小野 政徳, 藤原 浩
  • Total Pages: 3
  • Publisher: HORMONE FRONTIER IN GYNECOLOGY
• [Book] 【万能幹細胞・幹細胞とゲノム編集-再生医療の進歩が医療を変える】産婦人科領域における再生医療とゲノム編集子宮筋幹細胞の臨床的意義 (2017)
  • Author(s): 小野 政徳, 丸山 哲夫, 田中 守
  • Total Pages: 5
  • Publisher: 臨床婦人科産科
• [Book] 産科と婦人科 【子宮筋腫の最前線】 子宮筋腫の起源 幹細胞からの理解 (2016)
  • Author(s): 小野政徳、丸山哲夫、田中守
  • Total Pages: 5
  • Publisher: 診断と治療社
• [Remarks] 金沢大学医薬保健研究域医学系産科婦人科学教室
  • URL: http://obgyn.w3.kanazawa-u.ac.jp/introduction/dispensary/index.php